POU3F4

protein-coding

POU class 3 homeobox 4, the group of POU class homeoboxes and pseudogenes

Gene summary

This gene encodes a member of the POU-III class of neural transcription factors. This family member plays a role in inner ear development. The protein is thought to be involved in the mediation of epigenetic signals which induce striatal neuron-precursor differentiation. Mutations in this gene are associated with X chromosome-linked nonsyndromic mixed deafness. [provided by RefSeq, Dec 2012]

Previous symbols:

DFN3

MANE transcript

NM_000307.5

Inheritance

XL, Mitochondrial

ClinVar variants

P:119U:68B:38

Top phenotype

Deafness, X-linked 2

gnomAD constraint

pLI —, LoF o/e 0.15

Max pathogenic AF

—

Genomic locus

chrX:83,508,290-83,512,127

External References & Databases

Ensembl (ENSG00000196767)

Transcript & Mutation Effects

hg38 • Region Span ~3.8 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

X-linked mixed hearing loss with perilymphatic gusherSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010576

Submitter: PanelApp Australia

choroideremia-deafness-obesity syndromeSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010558

Submitter: Orphanet

nonsyndromic genetic hearing lossDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0019497

Submitter: ClinGen

The POU3F4 gene has been associated with X-linked nonsyndromic hearing loss using the ClinGen Clinical Validity Framework as of 9/25/2017. This association was made using case-level data only. At least 10 missense, frameshift, nonsense variants have been reported in humans. POU3F4 was first associated with this disease in humans as early as 1995 (de Kok et al.). Association is seen in at least 10 probands in 3 publications (7839145, 7581392, 27941975). Variants in this gene segregated with disease in 6 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence and/or experimental evidence (12 pts.) has been reached. This gene-disease association is supported by a spontaneous mouse model and a null mouse model, both with hearing loss, as well as other relevant expression and protein interaction studies. In summary, POU3F4 is definitively associated with X-linked nonsyndromic hearing loss. This classification was approved by the ClinGen Hearing Loss Working Group on 1/5/2018.

X-linked mixed hearing loss with perilymphatic gusherSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010576

Submitter: Labcorp Genetics (formerly Invitae)

mitochondrial non-syndromic sensorineural hearing lossSUPPORTIVE

Inheritance Pattern: Mitochondrial

Disease ID:MONDO:0010779

Submitter: Orphanet

Clinical Genomic Database (CGD)

Deafness, X-linked 2XL

Manifestation: Audiologic/Otolaryngologic

Intervention: Audiologic/Otolaryngologic

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; It has been suggested that that stapes surgery should not be performed due to a high likelihood of complications (the use of cochlear implants has been reported as beneficial)

Refs: 5173351; 6662621; 1922747; 7839145; 7581392; 19438930; 19671658; 19930154; 20412083; 21193157; 21250553; 21555964; 23076972; 23606368

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to POU3F4 variants in ClinVar

13 Conditions Cataloged

X-linked mixed hearing loss with perilymphatic gusherTotal: 105

not providedTotal: 88

not specifiedTotal: 23

Inborn genetic diseasesTotal: 23

POU3F4-related disorderTotal: 18

Rare genetic deafnessTotal: 7

Nonsyndromic genetic hearing lossTotal: 2

X-linked nonsyndromic hearing lossTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000307.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			9 clinvar	27 clinvar	2 clinvar	38
missense	7 clinvar	27 clinvar	55 clinvar	6 clinvar	3 clinvar	98
nonsense	22 clinvar	6 clinvar	2 clinvar			30
start loss			1 clinvar			1
frameshift	45 clinvar	12 clinvar	1 clinvar			58
splice donor/acceptor (+/-2bp)						0
Total	74	45	68	33	5	225

Highest pathogenic variant AF is 0.0000045894467

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 2 of 2 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000307.5	RefSeq	NP_000298.3	1	MANE Select
ENST00000644024.2	Ensembl	ENSP00000495996.1	1	MANE Select

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

regulation of transcription by RNA polymerase II
transcription by RNA polymerase II
sensory perception of sound
forebrain neuron differentiation
cochlea morphogenesis

Molecular Function

RNA polymerase II regulatory region sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
AT DNA binding
DNA-binding transcription factor activity
protein binding

Cellular Component

nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000373200
Coding exons: 1
Length: 1507
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.93	83	149	0.556	0.0000107	2350
Missense (PolyPhen)		17	60.329	0.28179		984
Synonymous	-0.572	75	69.0	1.09	0.00000532	737
Loss of Function	2.07	1	6.83	0.146	4.37e-7	106

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Probable transcription factor which exert its primary action widely during early neural development and in a very limited set of neurons in the mature brain.;

Recessive Scores

pRec: 0.110

Intolerance Scores

RVIS EVS: 0.13
RVIS percentile EVS: 62.74

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.539

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium